Functional impairment in tendons, such as those which control movement in the heel, elbow and shoulder represents a major health care problem. It is now widely believed that tendon overuse, as seen in sports (tennis elbow) or work related (carpal tunnel) activities, is the initiating factor for development of tendinopathy. This appears to be true, at least for the expanding number of patients in the vulnerable 30-50 year age group. A pathogenic pathway, favored by most in the field, is that overuse results in persistent micro- injury of tendon collagen fibers and that this wounding precipitates a series o cellular responses which result in further loss of tissue material properties and chronic pain. Our long-term goal is to determine whether the aberrant cell responses which accompany tendinopathies, can be redirected from degeneration to healing by the application of tailored biologic and/or biomechanical therapies. We are optimistic about a successful outcome of our studies since we believe that we have uncovered a central pathogenic pathway to tendinopathy which we anticipate will be amenable to such therapeutic control. The pathogenic pathway involves the accumulation of deposits we term ARDs, or aggrecan-rich deposits in the tendon matrix. This pathway has emerged from studies on equine tendinopathy in a susceptible breed of horses. We are pursuing mechanistic studies in wild type and ADAMTS5-deficient mice which exhibit tendon changes (biomechanical and biochemical) that mimic the human pathology. The mechanistic pathway under study suggests that both mechanical loading (exercise) and ADAMTS5 pathway activation are required to eliminate the ARDs (pericellular aggrecan accumulation). We are working on therapeutic approaches to eliminate these deposits via different mechanical loading modes (eccentric versus concentric exercise) as well as by direct injection of aggrecanolytic agents. Furthermore, we will directly apply the knowledge gained from these murine studies in order to examine the efficacy of mechanobiologic strategies to treat human tendinopathic tissues.